T-Cell Priming Technology Strengthens Pandemic Preparedness
A novel vaccine approach could offer cross-reactive protection against viruses of the same family, as well as variants.
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The threat of a pandemic occurring in the next few decades is ever-present and could be increasing due to factors such as climate change and urbanization. The number of “priority pathogens” that could cause a future pandemic now includes more than 30 infectious agents, highlighting the need for new strategies and technologies to tackle emerging and reemerging infectious diseases.
Professor Thomas Rademacher, co-founder, executive director and CEO at Gylden Pharma Limited hopes that T-cell priming vaccine technology that evokes the course of the cellular immune system’s "first responders" prompted by natural infection may hold a solution. Technology Networks spoke to Rademacher to learn more about this technology and its potential to strengthen preparedness for future pandemics.
For those unfamiliar with Gylden Pharma, could you tell us more about its T-cell priming vaccine technology?
Thomas Rademacher, PhD, MD (TR):
The first time you get exposed to a virus, antibodies don't show up until a few weeks later – they're the reserve troops. The first responders are your immune cells, particularly your CD8+ T cells which kill the infected cell.
Gylden has developed a vaccine technology to activate naïve T cells within a patient with specificity to a virus. In other words, our vaccines are designed to give a person access to virus-specific first responders before an infection occurs.
If you're not vaccinated, you depend on your environmental exposures to build up immunity and there is a race to whether the T cells can get to the infected cell before the infection spreads. On the other hand, if these T cells are present from day zero, as our vaccines would allow, we can prevent the infection from spreading and causing symptoms – we call this T-cell priming.
Our vaccine’s mechanism of action operates by raising a person’s immune set point by creating a pre-existing population of virus-specific CD8+ T cells that, upon subsequent pathogen encounter, can immediately kill infected cells before they can release virions.
The other way to achieve T-cell priming is using attenuated viruses. These come with risks, for example, in the oral poliovirus vaccine there is a rare chance that the weakened virus can mutate into a stronger version that can cause polio as opposed to protecting from the disease. Our vaccines remove this risk while priming T cells for lifetime protection from a disease.
BF:
TR:
Antibodies act as the immune system's last resort to an infection. Viruses tend to live inside of cells, moving between cells to travel around the body. However, viruses are released into the bloodstream if you have a catastrophic viral infection. This is known as viremia, and in response, the body makes antibodies as a last-ditch attempt to destroy the infection. If you're a young child or have a compromised immune system and your T cells can't handle an infection, that’s when you need antibodies.
However, some viruses have learned to use the antibody response to their advantage. For example, there's dengue fever and dengue hemorrhagic fever. The first time you get dengue; you get sick but won’t develop dengue hemorrhagic fever. If you catch dengue a second time and it’s a different strain of the virus, you can develop dengue hemorrhagic fever. The reason for this is the dengue virus latches on to the antibodies that were generated during the first dengue infection and it uses them to become more infectious. This is the case with many flaviviruses such as influenza and is called antibody-dependent enhancement.
What's unique about our vaccine is that it focuses on predominantly priming the T-cell response rather than generating an antibody response. There is the infamous case of the 2017 dengue vaccine controversy involving Sanofi Pasteur’s Dengvaxia® (Dengue Tetravalent Vaccine). The vaccine used a live virus and produced both an antibody and a T-cell response. They rolled the vaccine out to children in the Philippines and it looked promising until the kids caught a different strain of dengue. The antibodies induced by the vaccine itself then significantly raised the risk of life-threatening dengue hemorrhagic fever. As a result, the Philippines Food and Drug Administration decided to revoke Dengvaxia’s Certificates of Product Registration. Our vaccine primes the T cell aspect of the immune system only and therefore does not cause side effects that arise from the antibody component.
BF:
TR:
When we talk about RNA viruses, many exist as an ensemble of genetically diverse, replicating populations known as mutant clouds. So right from square one, you are dealing with mutations, which are the lifeblood of RNA viruses. Unlike with DNA, there are no correction mechanisms with RNA, so every single residue of an RNA virus has a certain probability of mutation. In addition, RNA viruses are small, for example, dengue fever has just four proteins. A single RNA species doesn’t contain enough information to cause real issues, it needs to work as a herd. As RNA viruses replicate in the cell, they make different forms of themselves and what then pops out of that cell is not a single entity. These variants work together and to remove these viruses, the body does something very clever – it kills the infected cell without even looking at the virus itself.
Every strand of RNA that is going to be turned into protein goes through what's called a pioneer round of editing to make sure that the RNA is okay. The product of that editing phase generates peptides from the virus. These peptides then end up on the surface of the viral infected cell. As far as the body is concerned, a viral infected cell is a foreign object and the cell is marked for cell death.
Antibodies, on the other hand, must recognize intact variants. The virus therefore continuously changes its cell surface as a natural evasion mechanism. However, the basic building blocks of the virus remain the same. On the antibody level, different strains of a virus are not cross-reactive at all, but on the T-cell level, it's the same virus so mutations are pretty much irrelevant.
BF:
TR:
The microneedle patch is painless and therefore great for patient compliance. In addition, we want to be able to vaccinate people externally yet targeted to the source of infection. For example, if I contract influenza, how do we vaccinate so that I now have a T-cell army in my lungs? The key is tissue-resident T cells. These cells are spread throughout all your organs and lie waiting as first responders to infection. You can’t exactly vaccinate someone in their internal organs, instead, we use the skin – the largest immunologic organ in the body.
If you vaccinate into the epidermis, a signal tells T cells to home in on the infected organs, so you get tissue-resident T cells. The epidermis is also directly connected to the draining lymph nodes. It's a skin lymphatic injection, which was never possible before the development of microneedle technology.
BF:
What role do you envision Gylden’s technology playing in preparing for future pandemics?
TR:
We’ve set out to create a repository of potential pandemic vaccines. We’ve designed vaccines for some very strange pathogens and someone might need them one day. The beauty of this technology is that once we’ve made the vaccine, it’s stable. If we think about the Ebola outbreak in 2005, some of the big pharma companies spent vast amounts of money on making an Ebola vaccine. However, by the time they had made the vaccine, there were no more Ebola cases so they couldn’t test it. Our approach is to have these vaccines ready in a repository that you could then test and rapidly deploy at the time of the original outbreak.
In addition, if we consider dengue, around 4 billion people are living in areas with a risk of infection. Everybody that gets our dengue vaccine is going to have their immune set point raised. If you live in Brazil, by the time you're 18 years old, you're likely to be immune to dengue because you've been bitten randomly by enough little dengue-carrying mosquitos to give you immunity. Our vaccine does what the mosquito takes 18 years to do and is designed to mimic natural immunity to enable a rapid response to future infections.
